Diabetes mellitus is a highly prevalent systemic disease that often causes lesions in several organs, particularly the retina, kidney, nerves and vascular system. Diabetes complications are usually divided into: a) acute complications, such as hypoglycemia, ketoacidosis and hyperosmolar coma; b) chronic or late complications, in turn divided into microangiopathic complications (nephropathy, retinopathy, and neuropathy), macroangiopathic complications (cardiovascular disease) and diabetic foot (macro- and microangiopathy).
The enormous social-health impact of diabetes is due to these chronic complications, mainly ocular (retinopathy), renal (nephropathy) and vascular (atherosclerosis) complications. Current approaches for treating diabetes, such as strict glucose and hypertension control, successfully stop disease progression but do not prevent the onset of chronic complications in many cases, particularly retinopathy, cardiovascular events or the progression of patients to renal failure and even their participation in dialysis and transplant programs.
Diabetic foot is one of the most common complications of diabetes which causes significant morbidity and a high risk of amputation and the treatment of which requires a multidisciplinary approach.
Diabetic retinopathy is the most common complication of diabetes and one of the main causes of blindness worldwide. Hyperglycemia per se and the metabolic pathways directly related to it intervene in the etiopathogenesis of diabetic retinopathy, causing damage in the capillary bed located in the inner retina (microangiopathic lesion). Diabetic retinopathy has been conventionally considered as a microangiopathic disease of the retina. However, current evidence indicates that neurodegeneration is an early phenomenon in the pathogenesis of diabetic retinopathy participating in the development of microvascular alterations. There are currently no specific treatments for the initial phases of diabetic retinopathy. Furthermore, the specific treatments indicated in advanced phases of the disease (laser photocoagulation, intravitreal injections of agents such as the anti-VEGF—“vascular endothelial growth factor” antibodies—or corticoids or vitrectomy) have a limited effectiveness and a high rate of side effects. Non-invasive therapeutic approaches would be necessary to prevent or treat diabetic retinopathy in the initial phases (neurodegeneration). In this sense, topical ocular administration (eye drops) would be the most suitable route due to its non-invasive nature as it would prevent systemic side effects.
In addition to diabetic retinopathy, there are other diseases presenting with neurodegeneration of the retina such as age-related macular degeneration (AMD), glaucoma and retinitis pigmentosa. Neurodegenerative diseases of the retina refer to the conditions of the retina characterized by progressive neuronal loss.
An in-depth analysis of these diseases, their critical sites, as well as the possible ways of protection and paths leading to recovery can be extracted from Schmidt et al., “Neurodegenerative Diseases of the Retina and Potential for the Protection and Recovery”, Current Neuropharmacology—2008, Vol. No. 6, pp.: 164-178.
In the case of diabetic retinopathy, neurodegeneration (loss of effective neurons) occurs in the early stages of the disease and causes functional abnormalities, such as the loss of chromatic discrimination and contrast sensitivity. These alterations can be detected by means of electrophysiological studies in diabetic patients even with less than two years of having diabetes, i.e., before the microvascular lesions can be detected under ophthalmologic examination. Furthermore, a delayed multifocal electroretinogram implicit time (mfERG-IT) predicts the development of early microvascular abnormalities. In addition, neuroretinal degeneration initiates and/or activates several metabolic and signaling pathways that will participate both in the microangiopathic process and in the disruption of the blood-retinal barrier (BRB).
The BRB is a structure of the eye that is very important in many diseases of the retina and, particularly, it is a crucial element in the pathogenesis of diabetic retinopathy. The BRB is made up of an inner BRB and an outer BRB. The inner BRB is formed by tight endothelial cell junctions. The outer BRB is made up of retinal pigment epithelium (RPE), the cells of which are also connected by tight junctions. Diabetic macular edema is due to the disruption of the BRB. Another common disease of the retina due to deterioration of the BRB which results in retinal edema is AMD. Furthermore, alteration of the BRB also occurs in many ocular situations, such as uveitis, trauma, intra-ocular surgery, vascular retinopathies, inherited dystrophies, etc. (Cunha-Vaz et al., “The Blood-Retinal Barrier in Retinal Disease”, European Ophthalmic Review—2009, Vol. No. 3, pp.:105-108).
Great effort is being made in recent years to know the molecular mechanisms involved in the development of diabetes complications, as well as to study their therapeutic potential.
The JAK/STAT (Janus Kinase/Signal Transducers and Activators of Transcription) signaling pathway is an important intracellular mechanism through which hyperglycemia and other factors contribute to the development of diabetes and its complications. JAK/STAT controls many cellular processes, such as proliferation, migration and differentiation, as well as the expression of inflammatory mediators. An increase in the expression and activation of members of the JAK/STAT pathway in atheromatous plaques, in renal biopsies of diabetic patients and in animal models of retinopathy and diabetic nephropathy has been described.
The SOCS (Suppressors Of Cytokine Signaling) protein family is the main endogenous mechanism for the negative regulation of the JAK/STAT pathway and alterations in the expression levels have been linked to different immune and inflammatory diseases. Experimental studies in genetically modified animals for SOCS family members have demonstrated a protective effect in pancreatic β-cells, with reduction in the incidence of diabetes (Flodström-Tullberg et al., Diabetes 2003; 52:2696-700) and in the associated renal damage (Ortiz-Muñoz et al., J Am SocNephrol 2010; 21:763-72), as well as an anti-atherosclerotic effect (Ortiz-Muñoz et al., ArteriosclerThromb Vasc Biol 2009; 29:525-531; Wesoly et al., Acta Biochim Pol 2010; 57(3):251-260; Liang et al., Int J Mol Med. 2013 May; 31(5):1066-74). This suggests a therapeutic potential of these endogenous proteins in diabetes complications.
The use of SOCS protein mimetic peptides has been described previously in experimental allergic encephalomyelitis, a model of multiple sclerosis (Mujtaba et al., J Immunol 2005; 175:5077-5086; Jager et al., J Neuroimmunol 2011; 232:108-118) and also in models of peripheral nerve damage (Girolami et al., ExpNeurol 2010; 223:173-182) and poxvirus viral infection (Ahmed et al., J Virol 2009; 83:1402-1415). SOCS polypeptides have also been described as inhibitors of cytokine-induced signaling, particularly in inflammation and viral or bacterial infections (US2009/0209458). Patent publication WO2010/151495 describes SOCS-1 or SOCS-3 antagonist peptides useful as antivirals. Patent document U.S. Pat. No. 8,420,096 describes a soluble peptide containing the SOCS1/SOCS3 sequence and a membrane translocation sequence and the potential use thereof for the treatment of immune diseases. Patent document US2009253618 also describes peptides of this type for use thereof in neuronal differentiation. Patent document US2009030179 uses several synthetic peptides of the SOCS-box region of these peptides as antimicrobial agents.
Despite the research existing in this field and the fact that the relationship between the JAK/STAT signaling pathway, SOCS proteins and diabetes has been postulated, the effective administration of a peptide per se for the prevention or treatment of ocular, renal or vascular complications of diabetes has not been described up until now. SOCS mimetic peptides have not been linked in any case to ocular disorders.